: A central hypothesis of modem neurobiology is that memory is stored through use-dependent changes in synaptic strength. Most work in this area has focused upon long-term potentiation and depression (LiP and LTD) of glutamatergic synapses. One limitation of this approach is that the brain regions where LTP and LTD are most often studied, such as the hippocampus, receive information that is so complex that its content cannot be easily characterized. In contrast, in the cerebellum it has been possible to propose a 'circuit diagram"""""""" for some simple forms of learning such as associative eyeblink conditioning and vestibulo-ocular reflex adaptation. For example, it is possible to assign the conditioned (CS) and unconditioned stimuli (US) in associative eyeblink conditioning to specific pathways (the mossy/parallel fiber system and climbing fibers, respectively). Over the last 20 years, a series of experiments which have used behavioral tasks together with extracellular recording, reversible inactivation and transgenic manipulations have produced a strong case that the cerebellum is critical for these forms of motor learning. In particular, LTD and LTP of the parallel fiber-Purkinje cell synapse have been implicated in acquisition and extinction of eyeblink conditioning, respectively. In recent years, this laboratory has used both electrode and optical recording in cerebellar slice and culture model systems to explore the molecular requirements for induction and expression of these phenomena. In particular, we (and others) have found that induction of LiP in the parallel fiber synapse requires a presynaptic cascade of Ca influx/adenylyl cyclase JJcAMP/PKA and that its expression is also presynaptic. In contrast, induction of LTD at this synapse is triggered by postsynaptic activation of mGluRl and AMPA receptors together with Ca influx, resulting in activation of PKC and consequent clathrin-mediated internalization of AMPA receptors. Along the way, we discovered a new form of plasticity, LTD at the climbing fiber-Purkinje cell synapse, which was not anticipated in models of cerebellar learning and which appears to share some induction requirements with parallel fiber LTD. We propose additional electrophysiological experiments to address the following central questions. Which proteins of the secretory apparatus are modulated by PKA to produce the increase in glutamate release that underlies expression of parallel fiber LIP? During LTD induction at parallel fiber synapses, what are the events which link PKC activation with AMPA receptor internalization? Can climbing fiber LTD be induced using patterns of stimulation that more closely approximate natural signals recorded in vivo? What are the consequences of climbing fiber LTD for the function of the Purkinje cells and the cerebellar cortical circuit? Are climbing fiber-evoked Ca signals altered? Is climbing fiber LTD expressed presynaptically or postsynaptically? Can it be detected with recordings of climbing fiber-evoked glutamate transporter currents in the Purkinje cell? Can it be blocked with manipulations that interfere with clathrin-mediated internalization of AMPA receptors (as previously seen with parallel fiber LTD)? At the level of basic science, these investigations are central to an understanding the cellular substrates of information storage. In addition, they have potential clinical relevance for both cerebellar motor disorders and disorders of learning and memory generally.
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